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  1. Article: Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia.

    Michel, Zachary / Raborn, Layne N / Spencer, Tiahna / Pan, Kristen / Martin, Daniel / Roszko, Kelly L / Wang, Yan / Robey, Pamela G / Collins, Michael T / Boyce, Alison M / de Castro Diaz, Luis Fernandez

    bioRxiv : the preprint server for biology

    2024  

    Abstract: Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants ... ...

    Abstract Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in
    Language English
    Publishing date 2024-02-28
    Publishing country United States
    Document type Preprint
    DOI 10.1101/2024.02.23.581225
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Identification of GNAS Variants in Circulating Cell-Free DNA from Patients with Fibrous Dysplasia/McCune Albright Syndrome.

    Roszko, Kelly L / Guthrie, Lori / Li, Xiaobai / Collins, Michael T / de Castro, Luis F / Boyce, Alison M

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2023  Volume 38, Issue 3, Page(s) 443–450

    Abstract: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic bone and endocrine disorder. Although most variants affect the GNAS R201 codon, obtaining a genetic diagnosis is difficult because not all cells harbor the variant, and an invasive ... ...

    Abstract Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic bone and endocrine disorder. Although most variants affect the GNAS R201 codon, obtaining a genetic diagnosis is difficult because not all cells harbor the variant, and an invasive biopsy may be required. We explored the presence of GNAS p.R201 variants in blood circulating cell free DNA (ccfDNA) using sensitive techniques of digital droplet polymerase chain reaction (PCR) (ddPCR) and competitive allele-specific TaqMan PCR (castPCR) in an effort to improve the genetic diagnosis of FD/MAS. We isolated ccfDNA from the plasma of 66 patients with a wide range of disease severity and performed both ddPCR and castPCR mutation analysis to search for GNAS p.R201H or R201C variants. We detected R201 variants in ccfDNA samples of 41 of 66 (62.1%) patients by either castPCR or ddPCR, and 45 of 66 (68.2%) of patients if the techniques were combined. Variant detection was more likely in patients with more severe disease. Skeletal disease burden score (SBS) was significantly higher in patients who had detectable variants, and SBS was a predictor of variant allele frequency. By ddPCR analysis, patients aged ≤30 years had higher detection rates, and higher variant allele frequencies, independent of disease burden. We detected variant DNA in only one patient with monostotic FD by ddPCR only. In summary, we have demonstrated that ccfDNA containing variant GNAS can be isolated from the plasma of patients with FD/MAS and that ddPCR and castPCR methods have similar variant detection rates. This methodology represents an important potential advancement in diagnosis for patients with FD/MAS, especially those younger than 30 years or with more severe disease. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.
    MeSH term(s) Humans ; Fibrous Dysplasia, Polyostotic/genetics ; Mutation ; GTP-Binding Protein alpha Subunits, Gs/genetics ; Chromogranins/genetics ; Fibrous Dysplasia of Bone/genetics ; Cell-Free Nucleic Acids/genetics
    Chemical Substances GTP-Binding Protein alpha Subunits, Gs (EC 3.6.5.1) ; Chromogranins ; Cell-Free Nucleic Acids ; GNAS protein, human (EC 3.6.1.-)
    Language English
    Publishing date 2023-01-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.4766
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

    Sheppard, Aaron J / Theng, Elizabeth H / Paravastu, Sriram S / Wojnowski, Natalia M / Farhadi, Faraz / Morris, Michael A / Hartley, Iris R / Gafni, Rachel I / Roszko, Kelly L / Collins, Michael T / Saboury, Babak

    Arteriosclerosis, thrombosis, and vascular biology

    2024  

    Abstract: Background: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific ... ...

    Abstract Background: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals.
    Methods: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCS
    Results: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment.
    Conclusions: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.
    Language English
    Publishing date 2024-04-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1221433-4
    ISSN 1524-4636 ; 1079-5642
    ISSN (online) 1524-4636
    ISSN 1079-5642
    DOI 10.1161/ATVBAHA.123.320455
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Hyperphosphatemic Tumoral Calcinosis: Pathogenesis, Clinical Presentation, and Challenges in Management.

    Boyce, Alison M / Lee, Alisa E / Roszko, Kelly L / Gafni, Rachel I

    Frontiers in endocrinology

    2020  Volume 11, Page(s) 293

    Abstract: Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of ... ...

    Abstract Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2)
    MeSH term(s) Calcinosis/pathology ; Calcinosis/therapy ; Disease Management ; Humans ; Hyperostosis, Cortical, Congenital/pathology ; Hyperostosis, Cortical, Congenital/therapy ; Hyperphosphatemia/pathology ; Hyperphosphatemia/therapy
    Language English
    Publishing date 2020-05-08
    Publishing country Switzerland
    Document type Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2592084-4
    ISSN 1664-2392
    ISSN 1664-2392
    DOI 10.3389/fendo.2020.00293
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Mosaic Effects of Growth Hormone on Fibrous Dysplasia of Bone.

    Roszko, Kelly L / Collins, Michael T / Boyce, Alison M

    The New England journal of medicine

    2018  Volume 379, Issue 20, Page(s) 1964–1965

    MeSH term(s) Fibrous Dysplasia of Bone/diagnostic imaging ; Fibrous Dysplasia of Bone/physiopathology ; Fibrous Dysplasia, Polyostotic/diagnostic imaging ; Fibrous Dysplasia, Polyostotic/physiopathology ; Hand/diagnostic imaging ; Human Growth Hormone/physiology ; Humans ; Male ; Pituitary Gland/diagnostic imaging ; Radiography ; Skull/diagnostic imaging ; Young Adult
    Chemical Substances Human Growth Hormone (12629-01-5)
    Language English
    Publishing date 2018-11-14
    Publishing country United States
    Document type Case Reports ; Letter
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMc1808583
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  6. Article ; Online: Efficacy and Safety of Encaleret in Autosomal Dominant Hypocalcemia Type 1.

    Gafni, Rachel I / Hartley, Iris R / Roszko, Kelly L / Nemeth, Edward F / Pozo, Karen A / Lombardi, Ed / Sridhar, Ananth V / Roberts, Mary S / Fox, Jonathan C / Collins, Michael T

    The New England journal of medicine

    2023  Volume 389, Issue 13, Page(s) 1245–1247

    MeSH term(s) Humans ; Calcium/metabolism ; Genes, Dominant/genetics ; Hypercalciuria/drug therapy ; Hypercalciuria/genetics ; Hypocalcemia/drug therapy ; Hypocalcemia/genetics ; Hypoparathyroidism/drug therapy ; Hypoparathyroidism/genetics ; Mutation ; Treatment Outcome ; Calcium-Regulating Hormones and Agents/therapeutic use
    Chemical Substances Calcium (SY7Q814VUP) ; Calcium-Regulating Hormones and Agents
    Language English
    Publishing date 2023-09-26
    Publishing country United States
    Document type Letter
    ZDB-ID 207154-x
    ISSN 1533-4406 ; 0028-4793
    ISSN (online) 1533-4406
    ISSN 0028-4793
    DOI 10.1056/NEJMc2302708
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article ; Online: Genotype-Phenotype Correlation in Fibrous Dysplasia/McCune-Albright Syndrome.

    Zhadina, Maria / Roszko, Kelly L / Geels, Raya E S / de Castro, Luis F / Collins, Michael T / Boyce, Alison M

    The Journal of clinical endocrinology and metabolism

    2021  Volume 106, Issue 5, Page(s) 1482–1490

    Abstract: Context: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain- ... ...

    Abstract Context: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder resulting in fractures, pain, and disability. There are no targeted or effective therapies to alter the disease course. Disease arises from somatic gain-of-function variants at the R201 codon in GNAS, replacing arginine by either cysteine or histidine. The relative pathogenicity of these variants is not fully understood.
    Objective: This work aimed 1) to determine whether the most common GNAS variants (R201C and R201H) are associated with a specific clinical phenotype, and 2) to determine the prevalence of the most common GNAS variants in a large patient cohort.
    Methods: This retrospective cross-sectional analysis measured the correlation between genotype and phenotype characterized by clinical, biochemical, and radiographic data.
    Results: Sixty-one individuals were genotyped using DNA extracted from tissue or circulating cell-free DNA. Twenty-two patients (36.1%) had the R201C variant, and 39 (63.9%) had the R201H variant. FD skeletal disease burden, hypophosphatemia prevalence, fracture incidence, and ambulation status were similar between the 2 groups. There was no difference in the prevalence of endocrinopathies, ultrasonographic gonadal or thyroid abnormalities, or pancreatic involvement. There was a nonsignificant association of cancer with the R201H variant.
    Conclusion: There is no clear genotype-phenotype correlation in patients with the most common FD/MAS pathogenic variants. The predominance of the R201H variant observed in our cohort and reported in the literature indicates it is likely responsible for a larger burden of disease in the overall population of patients with FD/MAS, which may have important implications for the future development of targeted therapies.
    MeSH term(s) Adolescent ; Adult ; Amino Acid Substitution ; Child ; Child, Preschool ; Chromogranins/genetics ; Cross-Sectional Studies ; Female ; Fibrous Dysplasia of Bone/epidemiology ; Fibrous Dysplasia of Bone/genetics ; Fibrous Dysplasia of Bone/pathology ; Fibrous Dysplasia, Polyostotic/epidemiology ; Fibrous Dysplasia, Polyostotic/genetics ; Fibrous Dysplasia, Polyostotic/pathology ; GTP-Binding Protein alpha Subunits, Gs/genetics ; Gene Frequency ; Genetic Association Studies ; Genetic Predisposition to Disease ; Humans ; Male ; Mutation, Missense ; Prevalence ; Retrospective Studies ; Severity of Illness Index ; Young Adult
    Chemical Substances Chromogranins ; GNAS protein, human (EC 3.6.1.-) ; GTP-Binding Protein alpha Subunits, Gs (EC 3.6.5.1)
    Language English
    Publishing date 2021-01-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/clinem/dgab053
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  8. Article ; Online: PTH 1-34 Replacement Therapy Has Minimal Effect on Quality of Life in Patients With Hypoparathyroidism.

    Roszko, Kelly L / Hu, Tiffany Y / Guthrie, Lori C / Brillante, Beth A / Smith, Michaele / Collins, Michael T / Gafni, Rachel I

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2021  Volume 37, Issue 1, Page(s) 68–77

    Abstract: In addition to hypocalcemia, patients with hypoparathyroidism report poor quality of life (QOL), complaining of fatigue and "brain fog." Parathyroid hormone (PTH) therapy can effectively manage hypocalcemia; however, the effects of PTH treatment on QOL ... ...

    Abstract In addition to hypocalcemia, patients with hypoparathyroidism report poor quality of life (QOL), complaining of fatigue and "brain fog." Parathyroid hormone (PTH) therapy can effectively manage hypocalcemia; however, the effects of PTH treatment on QOL are unclear. Thirty-one patients with hypoparathyroidism were treated in an open-label study with full replacement subcutaneous PTH 1-34 twice daily for up to 5.3 years, with individualized fine-dosing titration. Prior to initiation of PTH 1-34, conventional therapy was optimized. The 36-Item Short Form (SF-36) Health Survey, Fatigue Symptom Inventory (FSI), and 6-minute walk test (6MWT) were assessed at PTH start (baseline), every 6 months on PTH, and after PTH discontinuation. The SF-36 assesses physical function (PF), physical role limitations (RP), bodily pain (BP), general health (GH), vitality (VT), emotional role limitations (RE), social function (SF), and mental health (MH). Compared to population norms, patients at baseline had lower scores in RP, GH, VT, and MH (p < 0.05), consistent with impaired QOL. With PTH therapy, only GH at 6 months and VT at 12 months improved (p < 0.05). At the last treatment time point, RP, VT, and SF improved compared to baseline (p < 0.05). However, follow-up scores were unchanged from baseline or last PTH treatment, except for SF, which had decreased at follow-up compared to on-PTH (p < 0.05). On the FSI, there were no changes in fatigue frequency; perceived interference was improved at 12 and 18 months and composite severity was improved only at 60 months (p < 0.05). The 6MWT measures did not change. In conclusion, hypoparathyroidism is associated with decreased QOL. Despite the bias in open-label studies to predict improvements in QOL, PTH therapy had limited and non-sustained effects on QOL, inconclusive changes in fatigue experience, and no change in the 6MWT. Although PTH 1-34 can adequately manage the hypocalcemia in hypoparathyroidism, its effects on QOL appear to be minimal. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.
    MeSH term(s) Health Surveys ; Hormone Replacement Therapy ; Humans ; Hypoparathyroidism/drug therapy ; Quality of Life/psychology
    Language English
    Publishing date 2021-10-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Intramural
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.4452
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  9. Article ; Online: Hypoparathyroidism: Genetics and Diagnosis.

    Mannstadt, Michael / Cianferotti, Luisella / Gafni, Rachel I / Giusti, Francesca / Kemp, Elizabeth Helen / Koch, Christian A / Roszko, Kelly L / Yao, Liam / Guyatt, Gordon H / Thakker, Rajesh V / Xia, Weibo / Brandi, Maria-Luisa

    Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

    2022  

    Abstract: This narrative report summarizes diagnostic criteria for hypoparathyroidism and describes the clinical presentation and underlying genetic causes of the nonsurgical forms. We conducted a comprehensive literature search from January 2000 to January 2021 ... ...

    Abstract This narrative report summarizes diagnostic criteria for hypoparathyroidism and describes the clinical presentation and underlying genetic causes of the nonsurgical forms. We conducted a comprehensive literature search from January 2000 to January 2021 and included landmark articles before 2000, presenting a comprehensive update of these topics and suggesting a research agenda to improve diagnosis and, eventually, the prognosis of the disease. Hypoparathyroidism, which is characterized by insufficient secretion of parathyroid hormone (PTH) leading to hypocalcemia, is diagnosed on biochemical grounds. Low albumin-adjusted calcium or ionized calcium with concurrent inappropriately low serum PTH concentration are the hallmarks of the disease. In this review, we discuss the characteristics and pitfalls in measuring calcium and PTH. We also undertook a systematic review addressing the utility of measuring calcium and PTH within 24 hours after total thyroidectomy to predict long-term hypoparathyroidism. A summary of the findings is presented here; results of the detailed systematic review are published separately in this issue of JBMR. Several genetic disorders can present with hypoparathyroidism, either as an isolated disease or as part of a syndrome. A positive family history and, in the case of complex diseases, characteristic comorbidities raise the clinical suspicion of a genetic disorder. In addition to these disorders' phenotypic characteristics, which include autoimmune diseases, we discuss approaches for the genetic diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
    Language English
    Publishing date 2022-08-04
    Publishing country United States
    Document type Journal Article
    ZDB-ID 632783-7
    ISSN 1523-4681 ; 0884-0431
    ISSN (online) 1523-4681
    ISSN 0884-0431
    DOI 10.1002/jbmr.4667
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  10. Article: Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2.

    Roszko, Kelly L / Bi, Ruiye D / Mannstadt, Michael

    Frontiers in physiology

    2016  Volume 7, Page(s) 458

    Abstract: Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR), expressed on the surface of parathyroid ... ...

    Abstract Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR), expressed on the surface of parathyroid cells. In response to low ionized calcium, the parathyroids increase secretion of parathyroid hormone (PTH) which increases serum calcium. The CASR is also highly expressed in the kidneys, where it regulates the reabsorption of calcium from the primary filtrate. Autosomal dominant hypocalcemia (ADH) type 1 is caused by heterozygous activating mutations in the CASR which increase the sensitivity of the CASR to extracellular ionized calcium. Consequently, PTH synthesis and secretion are suppressed at normal ionized calcium concentrations. Patients present with hypocalcemia, hyperphosphatemia, low magnesium levels, and low or low-normal levels of PTH. Urinary calcium excretion is typically increased due to the decrease in circulating PTH concentrations and by the activation of the renal tubular CASR. Therapeutic attempts using CASR antagonists (calcilytics) to treat ADH are currently under investigation. Recently, heterozygous mutations in the alpha subunit of the G protein G11 (Gα11) have been identified in patients with ADH, and this has been classified as ADH type 2. ADH2 mutations lead to a gain-of-function of Gα11, a key mediator of CASR signaling. Therefore, the mechanism of hypocalcemia appears similar to that of activating mutations in the CASR, namely an increase in the sensitivity of parathyroid cells to extracellular ionized calcium. Studies of activating mutations in the CASR and gain-of-function mutations in Gα11 can help define new drug targets and improve medical management of patients with ADH types 1 and 2.
    Language English
    Publishing date 2016-10-18
    Publishing country Switzerland
    Document type Review ; Journal Article
    ZDB-ID 2564217-0
    ISSN 1664-042X
    ISSN 1664-042X
    DOI 10.3389/fphys.2016.00458
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